Tumor Suppressor Foxo3a Is Involved in the Regulation of Lipopolysaccharide-Induced Interleukin-8 in Intestinal HT-29 Cells

Snoeks, Lobke; Weber, Christopher R.; Turner, Jerrold R.; Bhattacharyya, Mitra; Wasland, Kaarin; Savkovic, Suzana D.

doi:10.1128/iai.00227-08

Cited by 48 publications

(66 citation statements)

References 59 publications

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“…In response to various stimuli, including TLR induction by microbial and viral pathogen, DCs produce proinflammatory cytokines and type I IFNs [30]. FOXO3 was previously reported to participate in the regulation of proinflammatory cytokine production in DCs and endothelial cells [10,29,31]. Here, we discover that FOXO3 also has the ability to inhibit IFN-β production in human MDDCs.…”

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confidence: 64%

Section: Discussionmentioning

confidence: 99%

“…FOXO3 was implicated in regulation of NF-κB inhibitors, IκBs [11,15], with inhibition of FOXO3 resulting in attenuated expression of IL-8 in LPS-treated intestinal epithelia [29]. It has also been proposed that FOXO3 prevents NF-κB translocation to the nucleus [15].…”

Section: Foxo3 Antagonizes Irf Activationmentioning

confidence: 99%

“…FOXO3 was previously reported to inhibit NF-κB activation, but mechanism responsible for this effect remains unclear. One of the suggested mechanisms of NF-κB inhibition is upregulation of IκB expression directly or indirectly [15,29], but this is believed to be cell-type-dependent mechanism [10,11]. Another direct physical interaction, which could prevent NF-κB from either entering the nucleus or, as demonstrated for FOXO4, or its binding to the DNA [11,15].…”

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confidence: 99%

“…Thus, it is possible that IKK-ε-mediated inhibition of FOXO3 thwarts cell-cycle arrest and apoptosis in cancer cells. In addition, it would favor the production of normally FOXO3 negatively controlled proinflammatory cytokines 21,29], facilitating tumorigenesis.In summary, we identify FOXO3 as a new IKK-ε-controlled check-point of IRF activation and regulation of IFN-β expression. FOXO3, which antagonizes NF-κB and IRF activities and hampers IFN-β and IFN-λ1 expression, is regulated by IKK-ε.…”

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FOXO3 as a new IKK‐ε‐controlled check‐point of regulation of IFN‐β expression

et al. 2012

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Cell survival transcription factor FOXO3 has been recently implicated in moderating proinflammatory cytokine production by dendritic cells (DCs), but the molecular mechanisms are unclear. It was suggested that FOXO3 could antagonize NF-κB activity, while IKK-β was demonstrated to inactivate FOXO3, suggesting a cross-talk between the two pathways. Therefore, FOXO3 activity must be tightly regulated to allow for an appropriate inflammatory response. Here, we show that in human monocyte-derived DCs (MDDCs), FOXO3 is able to antagonize signaling intermediates downstream of the Toll-like receptor (TLR) 4, such as NF-κB and interferon regulatory factors (IRFs), resulting in inhibition of interferon (IFN)-β expression.We also demonstrate that the activity of FOXO3 itself is regulated by IKK-ε, a kinase involved in IFN-β production, which phosphorylates and inactivates FOXO3 in response to TLR4 agonists. Thus, we identify FOXO3 as a new IKK-ε-controlled check-point of IRF activation and regulation of IFN-β expression, providing new insight into the role of FOXO3 in immune response control.Keywords: Activation-induced cell death r Cell volume regulation r T-cell response r Taurine transporter Supporting Information available online IntroductionThe FOXO transcription factors (FOXO1, FOXO3, FOXO4, and FOXO6) are involved in a wide range of cellular processes including cell-cycle arrest, apoptosis, oxidative stress detoxification, and cellular homeostasis [1][2][3]. Given their importance in such critical cellular functions, their activity is tightly regulated by posttranslational modifications, mainly via the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway [4]. In response to growth factors or cytokines, FOXO proteins are phosphorylated by AKT Correspondence: Dr. Lionel Luron e-mail: luron@ciml.univ-mrs.fr at three conserved serine/threonine residues (Thr 32 , Ser 253 , and Ser 315 of FOXO3) resulting in the protein inactivation via nuclear exclusion and subsequent degradation [5,6].More recently, FOXO factors have been shown to play a role in immunity and inflammation [7][8][9][10][11]. In addition to their critical role in homeostasis of immune-relevant cells including B and T cells [7][8][9], FOXOs are associated with inflammatory diseases [12,13]. Moreover, FOXO3 was identified as a key factor in regulation of the innate immune response [10]. In FOXO3-deficient mice, production of major proinflammatory cytokines IL-6 and TNF-α by dendritic cells (DCs) is increased in response to viral infection, resulting in a greater expansion of T-cell population [10]. Expression of proinflammatory cytokines as well as type I interferons (IFNs) in response to viral and microbial stimuli is regulated by a number of key transcription factors, including NF-κB and [20,21]. Interestingly, its overexpression in a breast cancer model system could functionally replace PI3K constitutive activation and prevent cell-cycle arrest and apoptosis [20], processes often mediated by FOXO3 target genes, such as Cyclin D, p27/KIP1, FasL, bim...

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confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Foxo3 Antagonizes Irf Activationmentioning

confidence: 99%

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confidence: 99%

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FOXO3 as a new IKK‐ε‐controlled check‐point of regulation of IFN‐β expression

et al. 2012

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Cardamonin induces G2/M arrest and apoptosis via activation of the JNK–FOXO3a pathway in breast cancer cells

Kong

et al. 2019

Cell Biology International

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Cardamonin (CD), a naturally occurring chalcone isolated from large black cardamom, was previously reported to suppress the proliferation of breast cancer cells. However, its precise molecular anti‐tumor mechanisms have not been well elucidated. In this study, we found that CD markedly inhibited the proliferation of MDA‐MB 231 and MCF‐7 breast cancer cells through the induction of G2/M arrest and apoptosis. Reactive oxygen species (ROS) plays a pivotal role in the inhibition of CD‐induced cell proliferation. Treatment with N‐acetyl‐cysteine (NAC), an ROS scavenger, blocked CD‐induced G2/M arrest and apoptosis in this study. Quenching of ROS by overexpression of catalase also blocked CD‐induced cell cycle arrest and apoptosis. We showed that CD enhanced the expression and nuclear translocation of Forkhead box O3 (FOXO3a) via upstream c‐Jun N‐terminal kinase, inducing the expression of FOXO3a and its target genes, including p21, p27, and Bim. This process led to the reduction of cyclin D1 and enhancement of activated caspase‐3 expression. The addition of NAC markedly reversed these effects, knockdown of FOXO3a using small interfering RNA also decreased CD‐induced G2/M arrest and apoptosis. In vivo, CD efficiently suppressed the growth of MDA‐MB 231 breast cancer xenograft tumors. Taken together, our data provide a molecular mechanistic rationale for CD‐induced cell cycle arrest and apoptosis in breast cancer cells.

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Forkhead box o3a suppresses lipopolysaccharide‐stimulated proliferation and inflammation in fibroblast‐like synoviocytes through regulating tripartite motif‐containing protein 3

Wang

Zhou

et al. 2019

Journal Cellular Physiology

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Fibroblast-like synoviocytes (FLS), synovial tissue-specific cells, are key effector cells during the pathogenesis of rheumatoid arthritis (RA). Our previous study has shown that tripartite motif-containing protein 3 (TRIM3) overexpression inhibits the proliferation and cytokine secretion of RA FLS. Experiments with gene knockout mice have suggested the important roles of forkhead box o3a (Foxo3a) in RA pathogenesis. The present study aimed to investigate the correlation between Foxo3a and TRIM3 during RA pathogenesis. The expression of Foxo3a and TRIM3 was reduced in RA synovial tissues in comparison to healthy controls, and Foxo3a messenger RNA (mRNA) expression in RA synovial tissues correlated positively with TRIM3 mRNA expression. We found that stimulation with lipopolysaccharide (LPS) caused the downregulation of Foxo3a and TRIM3 in FLS. Foxo3a or TRIM3 overexpression significantly attenuated the promoting effects of LPS on cell proliferation and the release of tumor necrosis factor-α, interleukin-6 (IL-6), and IL-1β. In addition, Foxo3a suppressed the inhibitory effects of LPS on the mRNA and protein levels of TRIM3, as well as the activity of TRIM3 promoter. Foxo3a or TRIM3 overexpression attenuated collagen-induced arthritis in rats. Furthermore, knockdown of TRIM3 significantly suppressed the effects of Foxo3a overexpression on LPS-activated FLS. In summary, our findings suggested that Foxo3a exerted inhibitory effects on LPS-induced proliferation and inflammation through increasing TRIM3 transcription. The decreased expression of Foxo3a may contribute to the RA pathogenesis. K E Y W O R D S cytokines, FLS, Foxo3a, proliferation, TRIM3

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Tumor Suppressor Foxo3a Is Involved in the Regulation of Lipopolysaccharide-Induced Interleukin-8 in Intestinal HT-29 Cells

Cited by 48 publications

References 59 publications

FOXO3 as a new IKK‐ε‐controlled check‐point of regulation of IFN‐β expression

FOXO3 as a new IKK‐ε‐controlled check‐point of regulation of IFN‐β expression

Cardamonin induces G2/M arrest and apoptosis via activation of the JNK–FOXO3a pathway in breast cancer cells

Forkhead box o3a suppresses lipopolysaccharide‐stimulated proliferation and inflammation in fibroblast‐like synoviocytes through regulating tripartite motif‐containing protein 3

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